Intracellular free Ca2+ is an important ion for controlling the contraction of cardiac muscle and various smooth muscles, the release of neurotransmitters, and the expression of genes. The concentration of such Ca2+ ion is regulated by Ca2+ pumps, Ca2+ channels and/or Na+/Ca2+ exchangers (NCX) present in the plasma membrane and the sarcoplasmic reticulum membrane. Among them, Na+/Ca2+ exchangers play a particularly important role in the contraction and relaxation of cardiac muscle and vascular smooth muscle (Ann. Rev. Physiol., vol. 52, p. 467 (1990)). At present, three NCX genes have been isolated and identified from mammals. Moreover, it is known that NCX1 protein is expressed at high levels in the brain, heart and kidney, NCX2 protein is expressed primarily in the brain and also expressed, but slightly, in visceral smooth muscle, and NCX3 protein is expressed primarily in the brain and also expressed, but slightly, in skeletal muscle (Jpn. J. Circ. Res, vol. 24, no. 3, p. 101 (2001); Am. J. Physiol., 272, C1250–C1261 (1997)).
As for NCX inhibitors, isothiourea derivatives such as 2-[2-[4-[nitrobenzyloxy]phenyl] ethyl]isothio-ureamethanesulfonate (K-BR7943) and phenoxyaniline derivatives such as 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) have been reported, and K-BR7943 has been confirmed to have efficacy in acute mycardial infarction models as well as brain and kidney ischemia/reperfusion models (J. Pharmacol. Exp. Ther., vol. 296, p. 412 (2001)). However, there is no report about the application of NCX inhibitors as therapeutic agents for hypertension.